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  • 1
    Abstract: Mutation of p53 is a frequent genetic lesion in pancreatic cancer being an unmet clinical challenge. Mutants of p53 have lost the tumour-suppressive functions of wild type p53. In addition, p53 mutants exert tumour-promoting functions, qualifying them as important therapeutic targets. Here, we show that the class I histone deacetylases HDAC1 and HDAC2 contribute to maintain the expression of p53 mutants in human and genetically defined murine pancreatic cancer cells. Our data reveal that the inhibition of these HDACs with small molecule HDAC inhibitors (HDACi), as well as the specific genetic elimination of HDAC1 and HDAC2, reduce the expression of mutant p53 mRNA and protein levels. We further show that HDAC1, HDAC2 and MYC directly bind to the TP53 gene and that MYC recruitment drops upon HDAC inhibitor treatment. Therefore, our results illustrate a previously unrecognized class I HDAC-dependent control of the TP53 gene and provide evidence for a contribution of MYC. A combined approach targeting HDAC1/HDAC2 and MYC may present a novel and molecularly defined strategy to target mutant p53 in pancreatic cancer.
    Type of Publication: Journal article published
    PubMed ID: 27721407
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  • 2
    Keywords: EXPRESSION ; NETWORK ; RISK ; DISCOVERY ; SCHIZOPHRENIA ; FRAMEWORK ; COPY-NUMBER VARIATION ; SPECTRUM DISORDERS ; DE-NOVO MUTATIONS ; NEURODEVELOPMENTAL DISORDERS
    Abstract: The genetic architecture of autism spectrum disorder involves the interplay of common and rare variants and their impact on hundreds of genes. Using exome sequencing, here we show that analysis of rare coding variation in 3,871 autism cases and 9,937 ancestry-matched or parental controls implicates 22 autosomal genes at a false discovery rate (FDR) 〈 0.05, plus a set of 107 autosomal genes strongly enriched for those likely to affect risk (FDR 〈 0.30). These 107 genes, which show unusual evolutionary constraint against mutations, incur de novo loss-of-function mutations in over 5% of autistic subjects. Many of the genes implicated encode proteins for synaptic formation, transcriptional regulation and chromatin-remodelling pathways. These include voltage-gated ion channels regulating the propagation of action potentials, pacemaking and excitability-transcription coupling, as well as histone-modifying enzymes and chromatin remodellers-most prominently those that mediate post-translational lysine methylation/demethylation modifications of histones.
    Type of Publication: Journal article published
    PubMed ID: 25363760
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  • 3
    Keywords: ENDOTHELIAL-CELLS ; EXPRESSION ; IN-VITRO ; GENE-EXPRESSION ; DENDRITIC CELLS ; PHOSPHORYLATION ; UP-REGULATION ; B-CELLS ; CHRONIC LYMPHOCYTIC-LEUKEMIA ; RHEUMATOID-ARTHRITIS ; CD40 STIMULATION ; PROLIFERATION CENTERS
    Abstract: PURPOSE: Environmental conditions in lymph node proliferation centers protect chronic lymphocytic leukemia (CLL) cells from apoptotic triggers. This situation can be mimicked by in vitro stimulation with CD40 ligand (CD40L) and interleukin 4 (IL-4). Our study investigates the impact of the drug leflunomide to overcome apoptosis resistance of CLL cells. EXPERIMENTAL DESIGN: CLL cells were stimulated with CD40L and IL-4 and treated with fludarabine and the leflunomide metabolite A771726. RESULTS: Resistance to fludarabine-mediated apoptosis was induced by CD40 activation alone stimulating high levels of BCL-XL and MCL1 protein expression. Apoptosis resistance was further enhanced by a complementary Janus-activated kinase (JAK)/STAT signal induced by IL-4. In contrast, CLL proliferation required both a CD40 and a JAK/STAT signal and could be completely blocked by pan-JAK inhibition. Leflunomide (A771726) antagonized CD40L/IL-4-induced proliferation at very low concentrations (3 mug/mL) reported to inhibit dihydroorotate dehydrogenase. At a concentration of 10 mug/mL, A771726 additionally attenuated STAT3/6 phosphorylation, whereas apoptosis of CD40L/IL-4-activated ("resistant") CLL cells was achieved with higher concentrations (IC(50): 80 mug/mL). Apoptosis was also effectively induced by A771726 in clinically refractory CLL cells with and without a defective p53 pathway. Induction of apoptosis involved inhibition of NF-kappaB activity and loss of BCL-XL and MCL1 expression. In combination with fludarabine, A771726 synergistically induced apoptosis (IC(50): 56 mug/mL). CONCLUSION: We thus show that A771726 overcomes CD40L/IL-4-mediated resistance to fludarabine in CLL cells of untreated as well as clinically refractory CLL cells. We present a possible novel therapeutic principle for attacking chemoresistant CLL cells. Clin Cancer Res; 18(2); 417-31. (c)2011 AACR.
    Type of Publication: Journal article published
    PubMed ID: 22072733
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  • 4
    ISSN: 0168-9002
    Source: Elsevier Journal Backfiles on ScienceDirect 1907 - 2002
    Topics: Physics
    Type of Medium: Electronic Resource
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  • 5
    Electronic Resource
    Electronic Resource
    Amsterdam : Elsevier
    Physics Letters A 126 (1988), S. 439-443 
    ISSN: 0375-9601
    Source: Elsevier Journal Backfiles on ScienceDirect 1907 - 2002
    Topics: Physics
    Type of Medium: Electronic Resource
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  • 6
    ISSN: 0731-7085
    Keywords: Dipivefrin hydrochloride ; HPLC ; degradation ; epinephrine ; mass spectrometry. ; stability
    Source: Elsevier Journal Backfiles on ScienceDirect 1907 - 2002
    Topics: Chemistry and Pharmacology , Medicine
    Type of Medium: Electronic Resource
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  • 7
    ISSN: 1011-1344
    Keywords: Cell culture ; Chenopodium ; Lutein ; Marchantia ; Photoinhibition ; Xanthophyll cycle pigments
    Source: Elsevier Journal Backfiles on ScienceDirect 1907 - 2002
    Topics: Biology , Chemistry and Pharmacology , Medicine
    Type of Medium: Electronic Resource
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  • 8
    ISSN: 0006-291X
    Source: Elsevier Journal Backfiles on ScienceDirect 1907 - 2002
    Topics: Biology , Chemistry and Pharmacology , Physics
    Type of Medium: Electronic Resource
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  • 9
    Publication Date: 2018-06-19
    Description: Myeloid-derived suppressor cells (MDSCs) are known suppressors of antitumor immunity, affecting amino acid metabolism and T cell function in the tumor microenvironment. However, it is unknown whether MDSCs regulate B cell responses during tumor progression. Using a syngeneic mouse model of lung cancer, we show reduction in percentages and absolute numbers of B cell subsets including pro–, pre–, and mature B cells in the bone marrow (BM) of tumor-bearing mice. The kinetics of this impaired B cell response correlated with the progressive infiltration of MDSCs. We identified that IL-7 and downstream STAT5 signaling that play a critical role in B cell development and differentiation were also impaired during tumor progression. Global impairment of B cell function was indicated by reduced serum IgG levels. Importantly, we show that anti–Gr-1 Ab-mediated depletion of MDSCs not only rescued serum IgG and IL-7 levels but also reduced TGF-β1, a known regulator of stromal IL-7, suggesting MDSC-mediated regulation of B cell responses. Furthermore, blockade of IL-7 resulted in reduced phosphorylation of downstream STAT5 and B cell differentiation in tumor-bearing mice and administration of TGF-β–blocking Ab rescued these IL-7–dependent B cell responses. Adoptive transfer of BM-derived MDSCs from tumor-bearing mice into congenic recipients resulted in significant reductions of B cell subsets in the BM and in circulation. MDSCs also suppressed B cell proliferation in vitro in an arginase-dependent manner that required cell-to-cell contact. Our results indicate that tumor-infiltrating MDSCs may suppress humoral immune responses and promote tumor escape from immune surveillance.
    Print ISSN: 0022-1767
    Electronic ISSN: 1550-6606
    Topics: Medicine
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  • 10
    Publication Date: 2014-11-05
    Description: The genetic architecture of autism spectrum disorder involves the interplay of common and rare variants and their impact on hundreds of genes. Using exome sequencing, here we show that analysis of rare coding variation in 3,871 autism cases and 9,937 ancestry-matched or parental controls implicates 22 autosomal genes at a false discovery rate (FDR) 〈 0.05, plus a set of 107 autosomal genes strongly enriched for those likely to affect risk (FDR 〈 0.30). These 107 genes, which show unusual evolutionary constraint against mutations, incur de novo loss-of-function mutations in over 5% of autistic subjects. Many of the genes implicated encode proteins for synaptic formation, transcriptional regulation and chromatin-remodelling pathways. These include voltage-gated ion channels regulating the propagation of action potentials, pacemaking and excitability-transcription coupling, as well as histone-modifying enzymes and chromatin remodellers-most prominently those that mediate post-translational lysine methylation/demethylation modifications of histones.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4402723/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4402723/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉De Rubeis, Silvia -- He, Xin -- Goldberg, Arthur P -- Poultney, Christopher S -- Samocha, Kaitlin -- Cicek, A Erucment -- Kou, Yan -- Liu, Li -- Fromer, Menachem -- Walker, Susan -- Singh, Tarinder -- Klei, Lambertus -- Kosmicki, Jack -- Shih-Chen, Fu -- Aleksic, Branko -- Biscaldi, Monica -- Bolton, Patrick F -- Brownfeld, Jessica M -- Cai, Jinlu -- Campbell, Nicholas G -- Carracedo, Angel -- Chahrour, Maria H -- Chiocchetti, Andreas G -- Coon, Hilary -- Crawford, Emily L -- Curran, Sarah R -- Dawson, Geraldine -- Duketis, Eftichia -- Fernandez, Bridget A -- Gallagher, Louise -- Geller, Evan -- Guter, Stephen J -- Hill, R Sean -- Ionita-Laza, Juliana -- Jimenz Gonzalez, Patricia -- Kilpinen, Helena -- Klauck, Sabine M -- Kolevzon, Alexander -- Lee, Irene -- Lei, Irene -- Lei, Jing -- Lehtimaki, Terho -- Lin, Chiao-Feng -- Ma'ayan, Avi -- Marshall, Christian R -- McInnes, Alison L -- Neale, Benjamin -- Owen, Michael J -- Ozaki, Noriio -- Parellada, Mara -- Parr, Jeremy R -- Purcell, Shaun -- Puura, Kaija -- Rajagopalan, Deepthi -- Rehnstrom, Karola -- Reichenberg, Abraham -- Sabo, Aniko -- Sachse, Michael -- Sanders, Stephan J -- Schafer, Chad -- Schulte-Ruther, Martin -- Skuse, David -- Stevens, Christine -- Szatmari, Peter -- Tammimies, Kristiina -- Valladares, Otto -- Voran, Annette -- Li-San, Wang -- Weiss, Lauren A -- Willsey, A Jeremy -- Yu, Timothy W -- Yuen, Ryan K C -- DDD Study -- Homozygosity Mapping Collaborative for Autism -- UK10K Consortium -- Cook, Edwin H -- Freitag, Christine M -- Gill, Michael -- Hultman, Christina M -- Lehner, Thomas -- Palotie, Aaarno -- Schellenberg, Gerard D -- Sklar, Pamela -- State, Matthew W -- Sutcliffe, James S -- Walsh, Christiopher A -- Scherer, Stephen W -- Zwick, Michael E -- Barett, Jeffrey C -- Cutler, David J -- Roeder, Kathryn -- Devlin, Bernie -- Daly, Mark J -- Buxbaum, Joseph D -- 5UL1 RR024975/RR/NCRR NIH HHS/ -- MH077139/MH/NIMH NIH HHS/ -- MH089482/MH/NIMH NIH HHS/ -- MH095034/MH/NIMH NIH HHS/ -- P30 HD15052/HD/NICHD NIH HHS/ -- P50 HD055751/HD/NICHD NIH HHS/ -- R01 MH061009/MH/NIMH NIH HHS/ -- R01 MH083565/MH/NIMH NIH HHS/ -- R01 MH089482/MH/NIMH NIH HHS/ -- R01 MH094400/MH/NIMH NIH HHS/ -- R01 MH095797/MH/NIMH NIH HHS/ -- R01 MH097849/MH/NIMH NIH HHS/ -- R01 MH100229/MH/NIMH NIH HHS/ -- R01 NS073601/NS/NINDS NIH HHS/ -- R01MH083565/MH/NIMH NIH HHS/ -- R01MH089208/MH/NIMH NIH HHS/ -- R37 MH057881/MH/NIMH NIH HHS/ -- RC2MH089952/MH/NIMH NIH HHS/ -- T32 HG002295/HG/NHGRI NIH HHS/ -- U01 MH100209/MH/NIMH NIH HHS/ -- U01 MH100229/MH/NIMH NIH HHS/ -- U01 MH100233/MH/NIMH NIH HHS/ -- U01 MH100239/MH/NIMH NIH HHS/ -- U01MH100209/MH/NIMH NIH HHS/ -- U01MH100229/MH/NIMH NIH HHS/ -- U01MH100233/MH/NIMH NIH HHS/ -- U01MH100239/MH/NIMH NIH HHS/ -- U54 HG003067/HG/NHGRI NIH HHS/ -- UL1TR000445/TR/NCATS NIH HHS/ -- WT091310/Wellcome Trust/United Kingdom -- WT098051/Wellcome Trust/United Kingdom -- Howard Hughes Medical Institute/ -- England -- Nature. 2014 Nov 13;515(7526):209-15. doi: 10.1038/nature13772. Epub 2014 Oct 29.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25363760" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Child Development Disorders, Pervasive/*genetics/pathology ; Chromatin/*genetics/metabolism ; Chromatin Assembly and Disassembly ; Exome/genetics ; Female ; Genetic Predisposition to Disease/*genetics ; Germ-Line Mutation/genetics ; Humans ; Male ; Molecular Sequence Data ; Mutation/*genetics ; Mutation, Missense/genetics ; Nerve Net/metabolism ; Odds Ratio ; Synapses/*metabolism ; Transcription, Genetic/*genetics
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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